Structural genomics for drug design against the pathogen Coxiella burnetii
ABSTRACT Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical...
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| Veröffentlicht in: | Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2015-12, Vol.83 (12), p.2124-2136 |
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| creator | Franklin, Matthew C. Cheung, Jonah Rudolph, Michael J. Burshteyn, Fiana Cassidy, Michael Gary, Ebony Hillerich, Brandan Yao, Zhong-Ke Carlier, Paul R. Totrov, Maxim Love, James D. |
| description | ABSTRACT
Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/prot.24841 |
| format | Article |
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Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc.</description><identifier>ISSN: 0887-3585</identifier><identifier>EISSN: 1097-0134</identifier><identifier>DOI: 10.1002/prot.24841</identifier><identifier>PMID: 26033498</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>antibiotic ; antifolate ; Bacterial Proteins - chemistry ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Binding Sites ; Bioterrorism ; Computer Simulation ; Coxiella burnetii ; Coxiella burnetii - drug effects ; Coxiella burnetii - genetics ; Crystallography, X-Ray ; dihydrofolate reductase ; Drug Design ; Folic Acid Antagonists - chemistry ; Folic Acid Antagonists - pharmacology ; High-Throughput Screening Assays - methods ; Humans ; inhibitor ; Protein Conformation ; Tetrahydrofolate Dehydrogenase - chemistry ; X-ray crystallography ; X‐ray crystallography; dihydrofolate reductase; inhibitor; antifolate; antibiotic</subject><ispartof>Proteins, structure, function, and bioinformatics, 2015-12, Vol.83 (12), p.2124-2136</ispartof><rights>2015 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4941-81f52dce6828f606d26e339cff885e2a0463beee0f3cd93b4e0bd7e37e9c5e6d3</citedby><cites>FETCH-LOGICAL-c4941-81f52dce6828f606d26e339cff885e2a0463beee0f3cd93b4e0bd7e37e9c5e6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fprot.24841$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fprot.24841$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26033498$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Franklin, Matthew C.</creatorcontrib><creatorcontrib>Cheung, Jonah</creatorcontrib><creatorcontrib>Rudolph, Michael J.</creatorcontrib><creatorcontrib>Burshteyn, Fiana</creatorcontrib><creatorcontrib>Cassidy, Michael</creatorcontrib><creatorcontrib>Gary, Ebony</creatorcontrib><creatorcontrib>Hillerich, Brandan</creatorcontrib><creatorcontrib>Yao, Zhong-Ke</creatorcontrib><creatorcontrib>Carlier, Paul R.</creatorcontrib><creatorcontrib>Totrov, Maxim</creatorcontrib><creatorcontrib>Love, James D.</creatorcontrib><title>Structural genomics for drug design against the pathogen Coxiella burnetii</title><title>Proteins, structure, function, and bioinformatics</title><addtitle>Proteins</addtitle><description>ABSTRACT
Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc.</description><subject>antibiotic</subject><subject>antifolate</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding Sites</subject><subject>Bioterrorism</subject><subject>Computer Simulation</subject><subject>Coxiella burnetii</subject><subject>Coxiella burnetii - drug effects</subject><subject>Coxiella burnetii - genetics</subject><subject>Crystallography, X-Ray</subject><subject>dihydrofolate reductase</subject><subject>Drug Design</subject><subject>Folic Acid Antagonists - chemistry</subject><subject>Folic Acid Antagonists - pharmacology</subject><subject>High-Throughput Screening Assays - methods</subject><subject>Humans</subject><subject>inhibitor</subject><subject>Protein Conformation</subject><subject>Tetrahydrofolate Dehydrogenase - chemistry</subject><subject>X-ray crystallography</subject><subject>X‐ray crystallography; dihydrofolate reductase; inhibitor; antifolate; antibiotic</subject><issn>0887-3585</issn><issn>1097-0134</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0ctuEzEUBmALgWgobHgAZIkNQpri-2WJIiigiAINYml5PGdSl8lMantE-_Y4pO2CBWLlzXd-nd8HoeeUnFBC2JtdmsoJE0bQB2hBidUNoVw8RAtijG64NPIIPcn5khCiLFeP0RFThHNhzQJ9Oi9pDmVOfsAbGKdtDBn3U8Jdmje4gxw3I_YbH8dccLkAvPPlYqoSL6frCMPgcTunEUqMT9Gj3g8Znt2-x-j7-3fr5YdmdXb6cfl21QRhBW0M7SXrAijDTK-I6pgCzm3oe2MkME-E4i0AkJ6HzvJWAGk7DVyDDRJUx4_Rq0Nu7X01Qy5uG3PYrzLCNGdHtSGSMaH5f1BFjOZa20pf_kUvp1qsFqlKamktl7Sq1wcV0pRzgt7tUtz6dOMocftjuP0x3J9jVPziNnJut9Dd07vfr4AewK84wM0_otyXb2fru9DmMBNzgev7GZ9-OlWbSPfj86ljX6VcrS115_w3VpCjXw</recordid><startdate>201512</startdate><enddate>201512</enddate><creator>Franklin, Matthew C.</creator><creator>Cheung, Jonah</creator><creator>Rudolph, Michael J.</creator><creator>Burshteyn, Fiana</creator><creator>Cassidy, Michael</creator><creator>Gary, Ebony</creator><creator>Hillerich, Brandan</creator><creator>Yao, Zhong-Ke</creator><creator>Carlier, Paul R.</creator><creator>Totrov, Maxim</creator><creator>Love, James D.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201512</creationdate><title>Structural genomics for drug design against the pathogen Coxiella burnetii</title><author>Franklin, Matthew C. ; Cheung, Jonah ; Rudolph, Michael J. ; Burshteyn, Fiana ; Cassidy, Michael ; Gary, Ebony ; Hillerich, Brandan ; Yao, Zhong-Ke ; Carlier, Paul R. ; Totrov, Maxim ; Love, James D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4941-81f52dce6828f606d26e339cff885e2a0463beee0f3cd93b4e0bd7e37e9c5e6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>antibiotic</topic><topic>antifolate</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding Sites</topic><topic>Bioterrorism</topic><topic>Computer Simulation</topic><topic>Coxiella burnetii</topic><topic>Coxiella burnetii - drug effects</topic><topic>Coxiella burnetii - genetics</topic><topic>Crystallography, X-Ray</topic><topic>dihydrofolate reductase</topic><topic>Drug Design</topic><topic>Folic Acid Antagonists - chemistry</topic><topic>Folic Acid Antagonists - pharmacology</topic><topic>High-Throughput Screening Assays - methods</topic><topic>Humans</topic><topic>inhibitor</topic><topic>Protein Conformation</topic><topic>Tetrahydrofolate Dehydrogenase - chemistry</topic><topic>X-ray crystallography</topic><topic>X‐ray crystallography; dihydrofolate reductase; inhibitor; antifolate; antibiotic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Franklin, Matthew C.</creatorcontrib><creatorcontrib>Cheung, Jonah</creatorcontrib><creatorcontrib>Rudolph, Michael J.</creatorcontrib><creatorcontrib>Burshteyn, Fiana</creatorcontrib><creatorcontrib>Cassidy, Michael</creatorcontrib><creatorcontrib>Gary, Ebony</creatorcontrib><creatorcontrib>Hillerich, Brandan</creatorcontrib><creatorcontrib>Yao, Zhong-Ke</creatorcontrib><creatorcontrib>Carlier, Paul R.</creatorcontrib><creatorcontrib>Totrov, Maxim</creatorcontrib><creatorcontrib>Love, James D.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Proteins, structure, function, and bioinformatics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Franklin, Matthew C.</au><au>Cheung, Jonah</au><au>Rudolph, Michael J.</au><au>Burshteyn, Fiana</au><au>Cassidy, Michael</au><au>Gary, Ebony</au><au>Hillerich, Brandan</au><au>Yao, Zhong-Ke</au><au>Carlier, Paul R.</au><au>Totrov, Maxim</au><au>Love, James D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural genomics for drug design against the pathogen Coxiella burnetii</atitle><jtitle>Proteins, structure, function, and bioinformatics</jtitle><addtitle>Proteins</addtitle><date>2015-12</date><risdate>2015</risdate><volume>83</volume><issue>12</issue><spage>2124</spage><epage>2136</epage><pages>2124-2136</pages><issn>0887-3585</issn><eissn>1097-0134</eissn><abstract>ABSTRACT
Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>26033498</pmid><doi>10.1002/prot.24841</doi><tpages>13</tpages></addata></record> |
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| ispartof | Proteins, structure, function, and bioinformatics, 2015-12, Vol.83 (12), p.2124-2136 |
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| subjects | antibiotic antifolate Bacterial Proteins - chemistry Bacterial Proteins - genetics Bacterial Proteins - metabolism Binding Sites Bioterrorism Computer Simulation Coxiella burnetii Coxiella burnetii - drug effects Coxiella burnetii - genetics Crystallography, X-Ray dihydrofolate reductase Drug Design Folic Acid Antagonists - chemistry Folic Acid Antagonists - pharmacology High-Throughput Screening Assays - methods Humans inhibitor Protein Conformation Tetrahydrofolate Dehydrogenase - chemistry X-ray crystallography X‐ray crystallography dihydrofolate reductase inhibitor antifolate antibiotic |
| title | Structural genomics for drug design against the pathogen Coxiella burnetii |
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